The receptor for the type I insulin like growth factor (IGF-IR) plays a critical role in progression of malignant disease. Increased expression of IGF-IR and/or its ligands has been documented in many human malignancies and high plasma IGF-I levels were identified as a potential risk factor for malignancies such as breast, prostate and colon carcinomas (Samani et al., 2007, Endocr Rev, 28: 20-47). Recent data have shown that the IGF axis promotes tumor invasion and metastasis through several mechanisms, and it has been identified as a determinant of metastasis to several organ sites, particularly the lymph nodes and the liver (Long et al., 1998, Exp Cell Res, 238: 116-121; Wei, et al., 2006, Ann Surg Oncol, 13: 668-676; Samani et al., 2007, Endocr Rev, 28: 20-47; Reinmuth et al., 2002, Clin Cancer Res, 8: 3259-3269). The IGF receptor can affect metastasis by regulating tumor cell survival and proliferation in secondary sites and also by promoting angiogenesis and lymphangiogenesis either through direct action on the endothelial cells or by transcriptional regulation of vascular endothelial growth factors (VEGF) A and C (reviewed in Li, S. et al., In: Liver metastasis:Biology and Clinical Management 2011; Brodt P., Editor: 233-72)).
The IGF-IR ligands include three structurally homologous peptides IGF-I, IGF-II and insulin, but the receptor binds IGF-I with the highest affinity. The major site of endocrine production for IGF-I and IGF-II is the liver (Werner & Le Roith, 2000, Cell Mol Life Sci 57: 932-942), but autocrine/paracrine IGF-I production has been documented in extra-hepatic sites such as heart, muscle, fat, spleen and kidney. The physiological activities and bioavailability of IGF-I and IGF-II are modulated through their association with 6 secreted, high-affinity binding proteins (IGFBP1-6).
IGF-IR has been validated as a target for anti-cancer therapy in various tumor types. A number of IGF-IR inhibitors are in clinical or preclinical development (see, for example, Zha, J. and Lackner, M. R., Clinical Cancer Research 2010; 16: 2512-7; Gualberto, A. and Pollak, M., Oncogene 2009; 28: 3009-21; and Li, S. et al., In: Liver metastasis: Biology and Clinical Management 2011; Brodt P., Editor: 233-72). However, targeting the IGF-I system in vivo poses several challenges: First, due to the high degree of homology between the IGF-I and insulin receptors, drugs that target the IGF axis may also affect the insulin receptor/insulin axis with undesirable effects on glucose and lipid metabolism. Hyperglycemia has, in fact, been observed as one of the undesirable effects of anti-IGF-IR therapy (Karp, D. D. et al., J. Thorac. Oncol. 2009; 4: 1397-403; Bruchim, I., et al., Expert Opinion on Therapeutic Targets 2009; 13: 1179-92; Sachdev, D. and Yee, D., Mol. Cancer Ther. 2007; 6: 1-12; Rodon, J. et al., Mol. Cancer Ther. 2008; 7: 2575-88). Moreover, inhibition of IGF-I signaling may result in altered serum growth hormone levels leading to insulin insensitivity and could potentially cause a reduction in pancreatic insulin production and diabetes (Zha, J. and Lackner, M. R., Clinical Cancer Research 2010; 16: 2512-7). Second, the use of antibody-based therapy may result in ADCC reactions leading to hematological toxicity as observed in some trials (Reidy, D. L., et al., Journal of Clinical Oncology; 28: 4240-6; Zha, J. and Lackner, M. R., Clinical Cancer Research 2010; 16: 2512-7). Furthermore, some tumors also express isoform A of the insulin receptor (IR-A) that can bind IGF-II with high affinity and this may provide an alternate survival mechanism for cancer cells whose IGF-IR has been neutralized by antibody treatment or kinase inhibitors (Zha, J. and Lackner, M. R., Clinical Cancer Research 2010; 16: 2512-7).
The use of soluble receptors (decoys) to antagonize the activity of soluble ligands for treatment of malignant disease has been taught as a potential therapeutic treatment and has become an accepted form of therapy for some conditions. Decoy receptors can inhibit the biological activity of the cognate, membrane-bound receptors by binding and decreasing ligand bioavailability for the latter receptor (Rudge, et al., 2007, Proc Natl Acad Sci USA, 104: 18363-18370). Current examples include a soluble TNF receptor (Enbrel) that is in routine clinical use for the treatment of inflammatory conditions (Richard-Miceli, C. and Dougados, M., BioDrugs 2001; 15: 251-9), as well as a VEGF-Trap (Aflibercept) that is in clinical trials for the treatment of cancer and other conditions (Rudge, J. S. et al., Cold Spring Harbor Symposia on Quantitative Biology 2005; 70: 411-8). These reagents are advantageous over antibody-based therapy because they are highly specific, bind to the ligand with high affinity, and bypass some of the undesirable effects of reagents with off-target activity.
Thus, a soluble IGF-I receptor could potentially overcome some of the shortcomings of current IGF-targeting drugs, such as, for example, cross-reaction with the insulin system, ADCC-related hematological toxicity, and the compensatory effects of insulin receptor isoform A (IR-A).
It would be highly desirable therefore to be provided with a soluble IGF-1 receptor for treatment of angiogenic-associated disorders and malignant disease, including cancer and metastasis.